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Adenomyosis is a benign gynecological condition characterized by the proliferation of the endometrial stroma and glands into the myometrium, uterine volume enlargement, and peripheral smooth muscle hypertrophy. The typical clinical symptoms include chronic pelvic pain, abnormal uterine bleeding, and subfertility, all of which significantly impact quality of life. There are no effective prevention or treatment strategies for adenomyosis, partly due to a limited understanding of the pathological mechanisms underlying the initiation and progression of the disease. Given that signaling pathways play a crucial role in the development of adenomyosis, a better understanding of these signaling pathways is essential for identifying therapeutic targets and advancing drug development. The occurrence and progression of adenomyosis are closely linked to various underlying pathophysiological mechanisms, including proliferation, migration, invasion, fibrosis, angiogenesis, inflammation, oxidative stress, immune response, and epigenetic changes. This review summarizes the signaling pathways and targets associated with the pathogenesis of adenomyosis, including CXCL/CXCR, NLRP3, NF-κB, TGF-β/smad, VEGF, Hippo/YAP, PI3K/Akt/mTOR, JAK/STAT, and other relevant pathways. In addition, it identifies promising future targets for the development of adenomyosis treatment, such as m6A, GSK3β, sphks, etc. [ABSTRACT FROM AUTHOR]

A lack of regulation around greenhouse gas (GHG) emissions has led Australian companies to employ arbitrary targets for measuring GHG emissions reduction, which are not translating to the level of emissions reduction required to meet global targets. Despite the well accepted urgency of climate change action, there is a gap in literature with no studies discussing the effectiveness of the various targets for measuring GHG emissions to meet global emission reduction goal. Using correlation and ordinary least squares (OLS) regression analysis, our study of Australian Stock Exchange listed companies shows that the targets suggested by Task Force on Climate‐related Financial Disclosure (TCFD) are the most closely associated with the required emissions reduction. The findings from this study advocate that organisations adopt TCFD recommendations for achieving optimal reduction of greenhouse gas emissions to meet the global targets. Our findings should inform policymakers and practice to align targets to the TCFD recommendations to meet the global emissions reduction commitments and mitigate the most severe impacts of climate change. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR-T) cell therapy has been a milestone breakthrough in the treatment of hematological malignancies, offering an effective therapeutic option for multi-line therapy-refractory patients. So far, abundant CAR-T products have been approved by the United States Food and Drug Administration or China National Medical Products Administration to treat relapsed or refractory hematological malignancies and exhibited unprecedented clinical efficiency. However, there were still several significant unmet needs to be progressed, such as the life-threatening toxicities, the high cost, the laborintensive manufacturing process and the poor long-term therapeutic efficacy. According to the demands, many researches, relating to notable technical progress and the replenishment of alternative targets or cells, have been performed with promising results. In this review, we will summarize the current research progress in CAR-T eras from the “targets” to “alternative cells”, to “combinational drugs” in preclinical studies and clinical trials. [ABSTRACT FROM AUTHOR]

Hu Zhang,1,* Jingyi Xia,2,* Xueqing Wang,1 Yifan Wang,2 Jie Chen,3 Lin He,1 Jingying Dai2 1Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, People’s Republic of China; 2Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, People’s Republic of China; 3Central Laboratory, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jingying Dai, Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu, 610072, People’s Republic of China, Tel +86-15756317270, Email 741107213@qq.com Lin He, Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu, 610072, People’s Republic of China, Tel +86-17708130632, Email helin514@126.comAbstract: Hematological malignancies originate from the hematopoietic system, including lymphoma, multiple myeloma, leukaemia, etc. They are highly malignant with a high incidence, a poor prognosis and a high mortality. Although the novel therapeutic strategies have partly improved the clinical efficacy of hematological malignancies, patients still face up with drug resistance, refractory disease and disease relapse. Many studies have shown that exosomes play an important role in hematological malignancies. Exosomes are nanoscale vesicles secreted by cells with a size ranging from 40 to 160 nm. They contain various intracellular components such as membrane proteins, lipids, and nucleic acids. These nanoscale vesicles transmit information between cells with the cargos. Thus, they participate in a variety of pathological processes such as angiogenesis, proliferation, metastasis, immunomodulation and drug resistance, which results in important role in the pathogenesis and progression of hematological malignancies. Furthermore, exosomes and the components carried in them can be used as potential biomarkers for the diagnosis, therapeutic sensitivity and prognosis in hematological malignancies. In the therapy of hematologic malignancies, certain exosome are potential to be used as therapeutic targets, meanwhile, exosomes are suitable drug carriers with lipid bilayer membrane and the nanostructure. Moreover, the tumor-derived exosomes of patients with hematologic malignancies can be developed into anti-tumor vaccines. The research and application of exosomes in hematological malignancies are summarized and discussed in this review.Keywords: hematological malignancies, exosomes, biomarkers, targets, drug carriers, vaccines

The tumor microenvironment (TME) encompasses the complex and diverse surroundings in which tumors arise. Emerging insights highlight the TME's critical role in tumor development, progression, metastasis, and treatment response. Consequently, the TME has attracted significant research and clinical interest, leading to the identification of numerous novel therapeutic targets. Advances in molecular technologies now enable detailed genomic and transcriptional analysis of cancer cells and the TME and the integration of microenvironmental data to the tumor genomic landscape. This comprehensive review discusses current progress in targeting the TME for drug development, addressing associated challenges, strategies for modulating the pro-tumor microenvironment, and the discovery of new targets.

The non-ferrous metallurgy industry in Russia is undergoing profound changes due to geopolitical shifts, the transition to green energy, and the need to develop processing industries. Non-ferrous metals, as strategically important products, can play a decisive role in achieving the global goals of the Russian economy related to economic security, the development of domestic markets, the reconstruction of high-tech industries, the modernization of stably functioning industries, and the improvement of the quality of life for the population. The purpose of this research is to study the trends and risks affecting non-ferrous metal producers and to assess the opportunities and challenges for developing both external and domestic markets, ultimately aiming to ensure sustainable demand for the products of mining companies and metal producers. The primary research methods used include general scientific approaches such as comparative analysis, synthesis, and decomposition. This paper reviews the current state of Russia’s non-ferrous metallurgy sector and explores its development prospects, with a specific focus on Norilsk Nickel, a key player operating in the Arctic. The main results of the study include an assessment of the current global market for non-ferrous metals, their role in the energy transition, and the formation of a low-carbon economy. The study also analyzes and summarizes the challenges facing domestic non-ferrous metallurgy and suggests potential directions for its development in the current economic context. A critical analysis of the Strategy for the Development of the Metallurgical Industry of the Russian Federation for the Period up to 2030 reveals that several important aspects and issues are not adequately addressed in the document. For example, it lacks a strategic planning methodology and fails to consider the specific characteristics and potential of the Arctic’s non-ferrous mineral resource base. The practical significance of this study lies in clarifying the prospects for utilizing non-ferrous metals to support the revitalization of high-tech industries in the national economy.

The Kunming‐Montreal Global Biodiversity Framework lays out an ambitious set of goals and targets aimed at halting and reversing biodiversity loss. The extent of natural ecosystems has been selected as one of a small set of headline indicators against which countries will report progress under this framework. We evaluate the effectiveness with which this indicator is expected to capture the overall scope of the ecosystem‐focused component of Goal A, and interlinkages with the species‐focused component of this same goal, using extensive global data on the integrity, connectivity, and plant species composition of forests. Results generated for all forest‐supporting countries demonstrate that consideration of these additional factors can profoundly alter understanding of the state of forest biodiversity relative to that based on extent alone. Employment of ecosystem extent as a headline indicator must therefore be augmented by appropriate use of component and complementary indicators addressing other key dimensions of ecosystem change. [ABSTRACT FROM AUTHOR]

Background: Xiaojin Pill (XJP) is a traditional Chinese medicine prescribed for treating benign prostatic hyperplasia (BPH). It has been proven to have multiple effects, such as regulating sex hormone levels, exhibiting anti-tumor, anti-inflammatory, analgesic, and anti-platelet aggregation properties, and improving immunity. However, the material basis of XJP's therapeutic effect on BPH and its metabolic process in vivo remains to be clarified. At the same time, many microorganisms that exist in the urogenital tract, including those related to BPH, can also affect the health of the host. Methods: Using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), the chemical components of XJP were identified. A BPH model was created through bilateral testicular ablation and injections of testosterone propionate. A comprehensive evaluation of XJP efficacy was conducted using pathological ELISA, TUNEL, and immunohistochemical techniques. In addition, UPLC-MS metabolomics and 16S rRNA sequencing revealed the serum metabolic profile and intestinal microbiota composition. We performed a Spearman correlation coefficient analysis to highlight the interactions between "intestinal microbiota-serum factors" and "intestinal microbiota-metabolites." Results: XJP contains 91 compounds that alleviate pathologies of BPH in rats, decreasing prostate weight, index, and serum levels of Dihydrotestosterone (DHT), Prostate-Specific Antigen (PSA), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) levels. It inhibits prostatic epithelial cell apoptosis and downregulates Bax, TGF-β1, and IGF-1 proteins in the caspase-3 pathway. Metabolomics studies have revealed 10 upregulated and 10 downregulated metabolites in treated rats, with 5-methylcytosine, uracil, and cytosine enriched in pyrimidine metabolism. L-arginine plays a pivotal role in metabolic pathways encompassing pyrimidine metabolism, arginine biosynthesis, and the mammalian target of rapamycin (mTOR) signaling pathway. 16S rRNA sequencing revealed that XJP optimized the diversity and balance of intestinal flora in BPH rats by decreasing the Bacteroidetes/Firmicutes (B/F) ratio, enhancing the beneficial bacteria, such as Eggerthellaceae, Anaerovoracaceae, and Romboutsia, and suppressing the dysfunctional bacteria, such as Atopobiaceae, Prevotellaceae_NK3B31_group, Dorea, and Frisingicoccus. According to the Spearman correlation coefficient analysis, Lactobacillus was found to be most associated with serum factors, whereas Romboutsia showed the highest correlation with metabolites. This finding suggests that XJP modulates pyrimidine metabolism disorders in BPH rats, a regulation that aligns closely with Romboutsia, Prevotellaceae_NK3B31_group, Lactobacillus, Chujaibacter, and Enterorhabdus, thereby providing valuable biological insights. Conclusion: In summary, these findings indicate that XJP possesses a synergistic anti-BHP effect through its multi-component, multi-target, multi-gut microbiota, and multi-metabolic pathway properties. The effect involves the regulation of sex hormone levels, growth factors, and the anti-epithelial cell apoptosis process. The modulation of specific gut microbiota by the host and the involvement of multiple metabolic pathways are likely one of the significant mechanisms of XJP in treating BPH. Notably, pyrimidine metabolism and the intestinal microbial ecosystem are closely intertwined in this process. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) affects approximately 2 million people worldwide. Obesity is the major risk factor for CRC. In addition, obesity contributes to a chronic inflammatory stage that enhances tumor progression through the secretion of proinflammatory cytokines. In addition to an increased inflammatory response, obesity-associated cancer presents accrued molecular factors related to cancer characteristics, such as genome instability, sustained cell proliferation, telomere dysfunctions, angiogenesis, and microbial alteration, among others. Despite the evidence accumulated over the last few years, the treatments for obesity-associated CRC do not differ from the CRC treatments in normal-weight individuals. In this review, we summarize the current knowledge on obesity-associated cancer, including its epidemiology, risk factors, molecular factors, and current treatments. Finally, we enumerate possible new therapeutic targets that may improve the conditions of obese CRC patients. Obesity is key for the development of CRC, and treatments resulting in the reversal of obesity should be considered as a strategy for improving antineoplastic CRC therapies. [ABSTRACT FROM AUTHOR]

With the general improvement in living standards in recent years, people's living habits, including their dietary habits, have changed. More people around the world do not follow a healthy diet, leading to an increase in morbidity and even mortality due to digestive system diseases, which shows an increasing trend every year. The advantage of traditional Chinese medicine (TCM) in treating digestive system diseases is evident. Consequently, the mechanisms of action of single Chinese herbs and compound Chinese medicines have become the focus of research. The research method of the network pharmacology system was highly consistent with the holistic concept of TCM, and provided a new perspective and theoretical basis for basic research on digestive system diseases. This article summarizes the common databases currently used in research on TCM. It also briefly introduces the basic methods and technologies of network pharmacology studies. It also summarizes the advancements of network pharmacology technology through a comprehensive literature search on PubMed. Based on this analysis, we further explored the role of TCM in treating digestive system diseases, including chronic gastritis, gastric cancer, ulcerative colitis, and liver cirrhosis. This study provides new ideas and references for treating digestive system diseases with TCM in the future and serves as a reference for relevant researchers. [ABSTRACT FROM AUTHOR]

Phthalates are widespread and commonly used plasticizers that lead to adverse health effects. Several natural products provide a protective effect against phthalates. Moreover, microRNAs (miRNAs) are regulated by natural products and phthalates. Therefore, miRNAs' impacts and potential targets may underlie the mechanism of phthalates. However, the relationship between phthalate-modulated miRNAs and phthalate protectors derived from natural products is poorly understood and requires further supporting information. In this paper, we review the adverse effects and potential targets of phthalates on reproductive systems as well as cancer and non-cancer responses. Information on natural products that attenuate the adverse effects of phthalates is retrieved through a search of Google Scholar and the miRDB database. Moreover, information on miRNAs that are upregulated or downregulated in response to phthalates is collected, along with their potential targets. The interplay between phthalate-modulated miRNAs and natural products is established. Overall, this review proposes a straightforward pathway showing how phthalates modulate different miRNAs and targets and cause adverse effects, which are partly attenuated by several natural products, thereby providing a direction for investigating the natural product–miRNA–target axis against phthalate-induced effects.

Background: Antimicrobial peptides (AMPs) are a critical component of the innate immune system, playing a key role in defending against a variety of pathogenic microorganisms. While many AMPs act primarily on the cell membrane of target pathogens, leading to lysis and subsequent cell death, less is known about their nonlytic membrane activity. This nonlytic activity allows AMPs to target and disrupt bacterial cells without causing lysis, leading to bacterial death through alternative mechanisms.Understanding these nonlytic properties of AMPs is crucial, as they present a promising alternative to traditional antibiotics, which can induce bacterial resistance and have adverse effects on human health and the environment. The mechanisms by which AMPs exhibit nonlytic membrane activity are still being explored. However, it is believed that AMPs penetrate the bacterial membrane and interact directly with internal cellular components such as DNA, RNA, and various enzymes essential for microbial survival and replication. This interaction disrupts metabolic homeostasis, ultimately resulting in bacterial death.The nonlytic activity of AMPs also results in minimal damage to host cells and tissues, making them attractive candidates for the development of new, more effective antibiotics. This review emphasizes the mechanisms by which AMPs nonlytically target cellular components, including DNA, proteins, RNA, and other biomolecules, and discusses their clinical significance. Understanding these mechanisms may pave the way for developing alternatives to conventional antibiotics, offering a solution to the growing issue of antibiotic resistance.

Abstract Dilated cardiomyopathy (DCM) is a common cause of heart failure, thromboembolism, arrhythmias, and sudden cardiac death. The quality of life and long-term survival rates of patients with dilated DCM have greatly improved in recent decades. Nevertheless, the clinical prognosis for DCM patients remains unfavorable. The primary driving factors underlying the pathogenesis of DCM remain incompletely understood. The present study aimed to identify driving factors underlying the pathogenesis of DCM from the perspective of gene regulatory networks. Single-cell RNA sequencing data and bulk RNA data were obtained from the Gene Expression Omnibus (GEO) database. Differential gene analysis, single-cell genomics analysis, and functional enrichment analysis were conducted using R software. The construction of Gene Regulatory Networks was performed using Python. We used the pySCENIC method to analyze the single-cell data and identified 401 regulons. Through variance decomposition, we selected 19 regulons that showed significant responsiveness to DCM. Next, we employed the ssGSEA method to assess regulons in two bulk RNA datasets. Significant statistical differences were observed in 9 and 13 regulons in each dataset. By intersecting these differentiated regulons and identifying shared targets that appeared at least twice, we successfully pinpointed three differentially expressed targets across both datasets. In this study, we assessed and identified 19 gene regulatory networks that were responsive to the disease. Furthermore, we validated these networks using two bulk RNA datasets of DCM. The elucidation of dysregulated regulons and targets (CDKN1A, SAT1, ZFP36) enhances the molecular understanding of DCM, aiding in the development of tailored therapies for patients.

Dilated cardiomyopathy (DCM) is a common cause of heart failure, thromboembolism, arrhythmias, and sudden cardiac death. The quality of life and long-term survival rates of patients with dilated DCM have greatly improved in recent decades. Nevertheless, the clinical prognosis for DCM patients remains unfavorable. The primary driving factors underlying the pathogenesis of DCM remain incompletely understood. The present study aimed to identify driving factors underlying the pathogenesis of DCM from the perspective of gene regulatory networks. Single-cell RNA sequencing data and bulk RNA data were obtained from the Gene Expression Omnibus (GEO) database. Differential gene analysis, single-cell genomics analysis, and functional enrichment analysis were conducted using R software. The construction of Gene Regulatory Networks was performed using Python. We used the pySCENIC method to analyze the single-cell data and identified 401 regulons. Through variance decomposition, we selected 19 regulons that showed significant responsiveness to DCM. Next, we employed the ssGSEA method to assess regulons in two bulk RNA datasets. Significant statistical differences were observed in 9 and 13 regulons in each dataset. By intersecting these differentiated regulons and identifying shared targets that appeared at least twice, we successfully pinpointed three differentially expressed targets across both datasets. In this study, we assessed and identified 19 gene regulatory networks that were responsive to the disease. Furthermore, we validated these networks using two bulk RNA datasets of DCM. The elucidation of dysregulated regulons and targets (CDKN1A, SAT1, ZFP36) enhances the molecular understanding of DCM, aiding in the development of tailored therapies for patients. [ABSTRACT FROM AUTHOR]

Zebrafish being the best animal model to study, every attempt has been made to decipher the toxic mechanism of every fungicide of usage and interest. It is important to understand the multiple targets of a toxicant to estimate the toxic potential in its totality. A total of 22 fungicides of different classes like amisulbrom, azoxystrobin, carbendazim, carboxin, chlorothalonil, difenoconazole, etridiazole, flusilazole, fluxapyroxad, hexaconazole, kresoxim methyl, mancozeb, myclobutanil, prochloraz, propiconazole, propineb, pyraclostrobin, tebuconazole, thiophanate-methyl, thiram, trifloxystrobin and ziram were reviewed and analyzed for their multiple explored targets in zebrafish. Toxic end points in zebrafish are highly informative when it comes to network analysis. They provide a window into the molecular and cellular pathways that are affected by a certain toxin. This can then be used to gain insights into the underlying mechanisms of toxicity and to draw conclusions on the potential of a particular compound to induce toxicity. This knowledge can then be used to inform decisions about drug development, environmental regulation, and other areas of research. In addition, the use of zebrafish toxic end points can also be used to better understand the effects of environmental pollutants on ecosystems. By understanding the pathways affected by a given toxin, researchers can determine how pollutants may interact with the environment and how this could lead to health or environmental impacts. [ABSTRACT FROM AUTHOR]

Drug discovery is a key process, given the rising and ubiquitous demand for medication to stay in good shape right through the course of one's life. Drugs are small molecules that inhibit or activate the function of a protein, offering patients a host of therapeutic benefits. Drug design is the inventive process of finding new medication, based on targets or proteins. Identifying new drugs is a process that involves time and money. This is where computer-aided drug design helps cut time and costs. Drug design needs drug targets that are a protein and a drug compound, with which the interaction between a drug and a target is established. Interaction, in this context, refers to the process of discovering protein binding sites, which are protein pockets that bind with drugs. Pockets are regions on a protein macromolecule that bind to drug molecules. Researchers have been at work trying to determine new Drug Target Interactions (DTI) that predict whether or not a given drug molecule will bind to a target. Machine learning (ML) techniques help establish the interaction between drugs and their targets, using computer-aided drug design. This paper aims to explore ML techniques better for DTI prediction and boost future research. Qualitative and quantitative analyses of ML techniques show that several have been applied to predict DTIs, employing a range of classifiers. Though DTI prediction improves with negative drug target pairs (DTP), the lack of true negative DTPs has led to the use a particular dataset of drugs and targets. Using dynamic DTPs improves DTI prediction. Little attention has so far been paid to developing a new classifier for DTI classification, and there is, unquestionably, a need for better ones. [ABSTRACT FROM AUTHOR]

As links between genotype and phenotype, small-molecule metabolites are attractive biomarkers for disease diagnosis, prognosis, classification, drug screening and treatment, insight into understanding disease pathology and identifying potential targets. Metabolomics technology is crucial for discovering targets of small-molecule metabolites involved in disease phenotype. Mass spectrometry-based metabolomics has implemented in applications in various fields including target discovery, explanation of disease mechanisms and compound screening. It is used to analyze the physiological or pathological states of the organism by investigating the changes in endogenous small-molecule metabolites and associated metabolism from complex metabolic pathways in biological samples. The present review provides a critical update of high-throughput functional metabolomics techniques and diverse applications, and recommends the use of mass spectrometry-based metabolomics for discovering small-molecule metabolite signatures that provide valuable insights into metabolic targets. We also recommend using mass spectrometry-based metabolomics as a powerful tool for identifying and understanding metabolic patterns, metabolic targets and for efficacy evaluation of herbal medicine. [ABSTRACT FROM AUTHOR]

Play fighting has been one of the most intensely studied forms of play and so has provided some of our deepest insights into the understanding of play in general. As the label implies, this behavior resembles serious fighting, in that the animals compete for an advantage over one another, but unlike true aggression, for play fighting to remain playful, it also incorporates a degree of cooperation and reciprocity - restrained competition seems to be its hallmark. Despite these common features, it should be noted that both the advantage competed over and the mechanisms by which restraint is achieved varies across species. Such variation mitigates simple generalities. For example, how empirical support for a proposed adaptive function in one species not being replicated in another, is to be interpreted. What has emerged over the past few decades is that play fighting is diverse, varying across several dimensions, some superficial, some fundamental, making choosing species to compare a challenge. In this paper,we explore various design features that constitute play fighting and the ways these can be modified across different species and lineages of species. Given that a major pillar of ethology is that description precedes explanation, having a good grasp of the behavioral diversity of play fighting is an essential starting point for detailed analyses of the mechanisms and functions of play. We show that commonalities across species likely involve different mechanisms than do species idiosyncrasies, and that different styles of play fighting likely afford different adaptive opportunities. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) -T cell therapy has entered the breakthrough era, characterized by a blend of therapeutic opportunities and challenges. With the integration of genome-editing technology, CAR-T cells will be empowered to become super warriors in eradicating tumor cells and attacking various tumors, including T-cell malignancies and acute myeloid leukemia. Notably, the optimization of CAR-T cells, including efficacy, safety, and manufacturing speed, coupled with other therapeutic strategies such as radiotherapy, hematopoietic stem cell transplantation, small-molecule inhibitors, and bispecific antibodies, could revolutionize the therapeutic landscape of tumors. Consequently, next-generation cellular immunotherapy, including universal CAR-NK cells and synergistic combination approaches, are anticipated to significantly impact cancer treatment in the coming decade. Nevertheless, the failure rates of CAR-T therapy continue to be significant. The challenge lies in determining the optimal combination strategy and identifying reliable and robust biomarkers to effectively select the patients who will derive the greatest benefit from CAR-T therapy. Herein, we highlight recent innovations in CAR-T products, combination strategies and predictive biomarkers of response presented at the 2023 ASH Annual Meeting. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate targets through which Gualou Xiebai Banxia decoction aids in treating myocardial infarction (MI) using network pharmacology in combination with molecular docking. The principal active ingredients of Gualou Xiebai Banxia decoction were identified from the TCMSP database using the criteria of drug-likeness ≥30% and oral bioavailability ≥0.18. Interactions and pathway enrichment were investigated using protein–protein interaction (PPI) networks and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, respectively. Active component structures were docked with those of potential protein targets using AutoDock molecular docking relative softwares. HIF1A was of particular interest as it was identified by the PPI network, GO and KEGG pathway enrichment analyses. In conclusion, the use of network pharmacology prediction and molecular docking assessments provides further information on the active components and mechanisms of action Gualou Xiebai Banxia decoction. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury (ALI) is a serious illness that has few treatment options available. Tribuloside, a natural flavonoid extracted from the Tribulus Terrestris plant in China, is potent in addressing many health issues such as headaches, dizziness, itching, and vitiligo. Objective: This study intends to explore the mechanisms of action of Tribuloside in treating ALI through a combination of network pharmacology and experimental validation. Methods: We obtained the 2D structure and SMILES number of Tribuloside from the PubChem database. We used the SwissTargetPrediction database to identify pharmacological targets. We found 1215 targets linked to ALI by examining the GeneCards database. We used the String database and Cytoscape software to create the "drug or disease-target" network as well as the protein-protein interactions (PPI). Key targets were identified by evaluating associated biological processes and pathway enrichment. A Venny Diagram showed 49 intersection points between Tribuloside and ALI. Molecular docking with AutoDockTools found that Tribuloside had a high affinity for IL6, BCL2, TNF, STAT3, IL1B, and MAPK3, the top 6 targets in the PPI network by Degree values. To test Tribuloside's therapeutic efficacy in ALI, an acute lung damage model in mice was constructed using lipopolysaccharide. Tribuloside treatment reduced inflammatory cell infiltration, decreased fibrotic area, repaired damaged alveoli, and suppressed inflammatory factors IL-6, TNF-α, and IL-1β in the lungs through many pathways and targets. Conclusion: This study reveals that Tribuloside has the potential to treat ALI by targeting various pathways and targets, according to network pharmacology predictions and experimental confirmation. [ABSTRACT FROM AUTHOR]

The UK government's 25 Year Plan to Improve the Environment (25YEP), published in 2018, together with annual progress reports and subsequent periodic revisions, represent the most comprehensive and forward-looking single body of environmental legislation for the United Kingdom. The forthcoming update of the UK National Biodiversity Strategy and Action Plan (NBSAP) addressing targets for the Convention on Biological Diversity's Global Biodiversity Framework to 2030 is also an opportunity to revisit the monitoring framework developed for the 25YEP. Here, we present an evaluation of the goals, targets and indicators of the 25YEP in light of gaps, synergies and opportunities for aligning with the CBD 2030 Framework. We make a number of recommendations for adopting indicators already developed in the context of CBD targets that can also measure progress towards environmental targets within the UK, with a view to more holistic monitoring of biodiversity status and trends. Landscape-scale interventions and, in particular, improvements to farming—exemplified by the new Environmental Land Management Schemes—and fishing policies have the potential for the greatest enhancement to the state of the UK environment and the plants and wildlife within it. [ABSTRACT FROM AUTHOR]

Licorice, derived from the root of Glycyrrhiza uralensis Fisch, is a key Traditional Chinese Medicine known for its detoxifying, spleen-nourishing, and qi-replenishing properties. Licochalcone A (Lico A), a significant component of licorice, has garnered interest due to its molecular versatility and receptor-binding affinity. This review explores the specific roles of Lico A in various diseases, providing new insights into its characteristics and guiding the rational use of licorice. Comprehensive literature searches using terms such as “licorice application” and “pharmacological activity of Lico A” were conducted across databases including CNKI, PubMed, and Google Scholar to gather relevant studies on Lico A’s pharmacological activities and mechanisms. Lico A, a representative chalcone in licorice, targets specific mechanisms in anti-cancer and anti-inflammatory activities. It also plays a role in post-transcriptional regulation. This review delineates the similarities and differences in the anti-cancer and anti-inflammatory mechanisms of Lico A, concluding that its effects on non-coding RNA through post-transcriptional mechanisms deserve further exploration.

Abstract Background Myelodysplastic syndrome (MDS) is known to arise through the pathogenic bone marrow mesenchymal stem cells (MSC) by interacting with hematopoietic stem cells (HSC). However, due to the strong heterogeneity of MDS patients, it is difficult to find common targets in studies with limited sample sizes. This study aimed to describe sequential molecular changes and identify biomarkers in MSC of MDS transformation. Methods Multidimensional data from three publicly available microarray and TCGA datasets were analyzed. MDS-MSC was further isolated and cultured in vitro to determine the potential diagnostic and prognostic value of the identified biomarkers. Results We demonstrated that normal MSCs presented greater molecular homogeneity than MDS-MSC. Biological process (embryonic skeletal system morphogenesis and angiogenesis) and pathways (p53 and MAPK) were enriched according to the differential gene expression. Furthermore, we identified HOXB3 and HOXB7 as potential causative genes gradually upregulated during the normal-MDS-AML transition. Blocking the HOXB3 and HOXB7 in MSCs could enhance the cell proliferation and differentiation, inhibit cell apoptosis and restore the function that supports hematopoietic differentiation in HSCs. Conclusion Our comprehensive study of gene expression profiling has identified dysregulated genes and biological processes in MSCs during MDS. HOXB3 and HOXB7 are proposed as novel surrogate targets for therapeutic and diagnostic applications in MDS.

Adenomyosis is a benign gynecological condition characterized by the proliferation of the endometrial stroma and glands into the myometrium, uterine volume enlargement, and peripheral smooth muscle hypertrophy. The typical clinical symptoms include chronic pelvic pain, abnormal uterine bleeding, and subfertility, all of which significantly impact quality of life. There are no effective prevention or treatment strategies for adenomyosis, partly due to a limited understanding of the pathological mechanisms underlying the initiation and progression of the disease. Given that signaling pathways play a crucial role in the development of adenomyosis, a better understanding of these signaling pathways is essential for identifying therapeutic targets and advancing drug development. The occurrence and progression of adenomyosis are closely linked to various underlying pathophysiological mechanisms, including proliferation, migration, invasion, fibrosis, angiogenesis, inflammation, oxidative stress, immune response, and epigenetic changes. This review summarizes the signaling pathways and targets associated with the pathogenesis of adenomyosis, including CXCL/CXCR, NLRP3, NF-κB, TGF-β/smad, VEGF, Hippo/YAP, PI3K/Akt/mTOR, JAK/STAT, and other relevant pathways. In addition, it identifies promising future targets for the development of adenomyosis treatment, such as m6A, GSK3β, sphks, etc.

Metal ions are essential trace elements for all living organisms and play critical catalytic, structural, and allosteric roles in many enzymes and transcription factors. Mycobacterium tuberculosis (MTB), as an intracellular pathogen, is usually found in host macrophages, where the bacterium can survive and replicate. One of the reasons why Tuberculosis (TB) is so difficult to eradicate is the continuous adaptation of its pathogen. It is capable of adapting to a wide range of harsh environmental stresses, including metal ion toxicity in the host macrophages. Altering the concentration of metal ions is the common host strategy to limit MTB replication and persistence. This review mainly focuses on transcriptional regulatory proteins in MTB that are involved in the regulation of metal ions such as iron, copper and zinc. The aim is to offer novel insights and strategies for screening targets for TB treatment, as well as for the development and design of new therapeutic interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver cancer is one of the most difficult solid tumors to treat and is responsible for one-third of cancer-related deaths worldwide. In particular, the quest for effective therapeutic strategies for hepatocellular carcinoma, which often arises from a chronic inflammatory background, remains an open challenge. In this review, we aim to provide an overview of the current therapeutic options available, focusing on recent advances in targeted therapies and the pursuit of emerging potential targets. Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment. [ABSTRACT FROM AUTHOR]

Background: Advanced paramedic practitioners in critical care (APPCCs) are advanced clinical practitioners focused on the delivery of pre-hospital critical care. While working in an ambulance control room setting, APPCCs seek to identify emergency calls appropriate for operational APPCCs to attend. These would include out-of-hospital cardiac arrest (OHCA). Through interrogation of incoming emergency calls they are also able to identify OHCA calls where resuscitation may be futile. In these cases, and within a governance framework, they stand down multiple ambulance responders, leaving only the closest responding resource to attend, thereby ‘saving resources’ that can be re-directed to other waiting emergency calls. It is believed that this is the first initiative of this nature in the United Kingdom. Methods: A three-year retrospective service evaluation of data was undertaken. The aim was to quantify the number of ‘saved resources’, including both double crewed ambulances (DCAs) and solo (single-person) responders, and furthermore to equate those savings into potential hours saved, using average known job cycle times (JCTs). Additionally, safety was assessed by searching all mandated incident reports for occasions where, despite cancellation of resources by an APPCC, resuscitation was commenced by the first response to scene. Results: A total of 13,356 ambulance resources were saved. Of these, 6593 (49.4%) were DCAs and 6763 (50.6%) were solo responders. Using the average JCT for deceased patients of 104.8 minutes, the total time saving equated to 23,328.48 hours of work or 1944.04 12-hour shifts. When considering DCAs alone, the average JCT for obviously deceased patients was 110.9 minutes. This equates to 12,186.1 hours of work or 1015.5 12-hour shifts. A total of 15 incident reports were identified. All had been investigated, revealing appropriate decision making in cancelling ambulance resources. No patient harm was identified. [ABSTRACT FROM AUTHOR]

Obesity is a major risk factor for morbidity and mortality because it has a close relationship to metabolic illnesses, such as diabetes, cardiovascular diseases, and some types of cancer. With no drugs available, the mainstay of obesity management remains lifestyle changes with exercise and dietary modifications. In light of the tremendous disease burden and unmet therapeutics, fresh perspectives on pathophysiology and drug discovery are needed. The development of epigenetics provides a compelling justification for how environmental, lifestyle, and other risk factors contribute to the pathogenesis of obesity. Furthermore, epigenetic dysregulations can be restored, and it has been reported that certain natural products obtained from plants, such as tea polyphenols, ellagic acid, urolithins, curcumin, genistein, isothiocyanates, and citrus isoflavonoids, were shown to inhibit weight gain. These substances have great antioxidant potential and are of great interest because they can also modify epigenetic mechanisms. Therefore, understanding epigenetic modifications to target the primary cause of obesity and the epigenetic mechanisms of anti‐obesity effects with certain phytochemicals can prove rational strategies to prevent the disease and develop novel therapeutic interventions. Thus, the current review aimed to summarize the epigenetic mechanisms and advances in therapies for obesity based on natural products to provide evidence for the development of several potential anti‐obesity drug targets. [ABSTRACT FROM AUTHOR]

Economic development and increased stress have considerably increased the prevalence of psychiatric disorders in recent years, which rank as some of the most prevalent diseases globally. Several factors, including chronic social stress, genetic inheritance, and autogenous diseases, lead to the development and progression of psychiatric disorders. Clinical treatments for psychiatric disorders include psychotherapy, chemotherapy, and electric shock therapy. Although various achievements have been made researching psychiatric disorders, the pathogenesis of these diseases has not been fully understood yet, and serious adverse effects and resistance to antipsychotics are major obstacles to treating patients with psychiatric disorders. Recent studies have shown that the mammalian target of rapamycin (mTOR) is a central signaling hub that functions in nerve growth, synapse formation, and plasticity. The PI3K-AKT/mTOR pathway is a critical target for mediating the rapid antidepressant effects of these pharmacological agents in clinical and preclinical research. Abnormal PI3K-AKT/mTOR signaling is closely associated with the pathogenesis of several neurodevelopmental disorders. In this review, we focused on the role of mTOR signaling and the related aberrant neurogenesis in psychiatric disorders. Elucidating the neurobiology of the PI3K-AKT/mTOR signaling pathway in psychiatric disorders and its actions in response to antidepressants will help us better understand brain development and quickly identify new therapeutic targets for the treatment of these mental illnesses. [ABSTRACT FROM AUTHOR]

This study analyses the relationship between the physical education (PE) curriculum in secondary education in Spain and the Sustainable Development Goals (SDGs). The Physical education curriculum of compulsory secondary education, as well as the complementary materials, were analysed through document analysis. Although there is no explicit relationship, the analysis reveals links between curricular elements and SDGs targets, particularly with SDG 4 (Quality Education), 3 (Health and Well-being), and 5 (Gender Equality). Other SDGs, such as 10 (Reducing Inequalities) and 12 (Responsible Consumption), are less related. The social dimension of sustainable development is most closely linked to PE. A historical analysis of the treatment of sustainable development in PE curricula in Spain is also presented, examining how they have evolved over time. The manuscript helps clarify how teachers and researchers can mobilize competencies to address global challenges in students' lives as individuals and world citizens, fostering commitment and social responsibility. Furthermore, this work highlights the importance of integrating the SDGs into education and how PE can be a key tool in this process. [ABSTRACT FROM AUTHOR]

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Diabetes mellitus, the most prevalent endocrine disorder, not only impacts the retina but also significantly involves the ocular surface. Diabetes contributes to the development of dry eye disease and induces morphological and functional corneal alterations, particularly affecting nerves and epithelial cells. These changes manifest as epithelial defects, reduced sensitivity, and delayed wound healing, collectively encapsulated in the context of diabetic keratopathy. In advanced stages of this condition, the progression to corneal ulcers and scarring further unfolds, eventually leading to corneal opacities. This critical complication hampers vision and carries the potential for irreversible visual loss. The primary objective of this review article is to offer a comprehensive overview of the pathomechanisms underlying diabetic keratopathy. Emphasis is placed on exploring the redox molecular pathways responsible for the aberrant structural changes observed in the cornea and tear film during diabetes. Additionally, we provide insights into the latest experimental findings concerning potential treatments targeting oxidative stress. This endeavor aims to enhance our understanding of the intricate interplay between diabetes and ocular complications, offering valuable perspectives for future therapeutic interventions. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus can readily form biofilm which enhances the drug-resistance, resulting in life-threatening infections involving different organs. Biofilm formation occurs due to a series of developmental events including bacterial adhesion, aggregation, biofilm maturation, and dispersion, which are controlled by multiple regulatory systems. Rapidly increasing research and development outcomes on natural products targeting S. aureus biofilm formation and/or regulation led to an emergent application of active phytochemicals and combinations. This review aimed at providing an in-depth understanding of biofilm formation and regulation mechanisms for S. aureus, outlining the most important antibiofilm strategies and potential targets of natural products, and summarizing the latest progress in combating S. aureus biofilm with plant-derived natural products. These findings provided further evidence for novel antibiofilm drugs research and clinical therapies.

Peptide stapling, by employing a stable, preformed alpha-helical conformation, results in the production of peptides with improved membrane permeability and enhanced proteolytic stability, compared to the original peptides, and provides an effective solution to accelerate the rapid development of peptide drugs. Various reviews present peptide stapling chemistries, anchoring residues and one- or two-component cyclization, however, therapeutic stapled peptides have not been systematically summarized, especially focusing on various disease-related targets. This review highlights the latest advances in therapeutic peptide drug development facilitated by the application of stapling technology, including different stapling techniques, synthetic accessibility, applicability to biological targets, potential for solving biological problems, as well as the current status of development. Stapled peptides as therapeutic drug candidates have been classified and analysed mainly by receptor- and ligand-based stapled peptide design against various diseases, including cancer, infectious diseases, inflammation, and diabetes. This review is expected to provide a comprehensive reference for the rational design of stapled peptides for different diseases and targets to facilitate the development of therapeutic peptides with enhanced pharmacokinetic and biological properties.

Play fighting has been one of the most intensely studied forms of play and so has provided some of our deepest insights into the understanding of play in general. As the label implies, this behavior resembles serious fighting, in that the animals compete for an advantage over one another, but unlike true aggression, for play fighting to remain playful, it also incorporates a degree of cooperation and reciprocity – restrained competition seems to be its hallmark. Despite these common features, it should be noted that both the advantage competed over and the mechanisms by which restraint is achieved varies across species. Such variation mitigates simple generalities. For example, how empirical support for a proposed adaptive function in one species not being replicated in another, is to be interpreted. What has emerged over the past few decades is that play fighting is diverse, varying across several dimensions, some superficial, some fundamental, making choosing species to compare a challenge. In this paper, we explore various design features that constitute play fighting and the ways these can be modified across different species and lineages of species. Given that a major pillar of ethology is that description precedes explanation, having a good grasp of the behavioral diversity of play fighting is an essential starting point for detailed analyses of the mechanisms and functions of play. We show that commonalities across species likely involve different mechanisms than do species idiosyncrasies, and that different styles of play fighting likely afford different adaptive opportunities.

Abstract Acute pancreatitis (AP) is a common and life-threatening digestive disorder. However, its diagnosis and treatment are still impeded by our limited understanding of its etiology, pathogenesis, and clinical manifestations, as well as by the available detection methods. Fortunately, the progress of microenvironment-targeted nanoplatforms has shown their remarkable potential to change the status quo. The pancreatic inflammatory microenvironment is typically characterized by low pH, abundant reactive oxygen species (ROS) and enzymes, overproduction of inflammatory cells, and hypoxia, which exacerbate the pathological development of AP but also provide potential targeting sites for nanoagents to achieve early diagnosis and treatment. This review elaborates the various potential targets of the inflammatory microenvironment of AP and summarizes in detail the prospects for the development and application of functional nanomaterials for specific targets. Additionally, it presents the challenges and future trends to develop multifunctional targeted nanomaterials for the early diagnosis and effective treatment of AP, providing a valuable reference for future research. Graphical Abstract

Abstract Background Cancer-secreted exovesicles are important for cell-to-cell communication by altering cancer-related signalling pathways. Exovesicles-derived miRNAs (exomiRNAs)-target genes can be useful for diagnostic and prognostic purposes. Methods ExomiRNA from prostate cancer (PCa) cells (PC-3 and LNCaP) were quantified by qRT-PCR and compared to the healthy cell line RWPE-1 by using miRNome PCR 752 miRNAs Panel. MiRNet database was used to predict exomiRNA-target genes. ExomiRNA-target genes pathway functional enrichment was performed by using Reactome database and Enrichr platform. Protein–protein interaction analysis was carried out by using the STRING database. RNA target-gene sequencing data from The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) database was screened out in 465 PCa patients for candidate gene expression in prostate tumour (PT) tissue and non-pathologic prostate (N-PP) tissue. Signature gene candidates were statistically analysed for diagnosis and prognosis usefulness. Results A total of 36 exomiRNAs were found downregulated when comparing PCa cells vs a healthy cell line; and when comparing PC-3 vs LNCaP, 14 miRNAs were found downregulated and 52 upregulated. Reactome pathway database revealed altered pathways and genes related to miRNA biosynthesis, miRNA-mediated gene silencing (TNRC6B and AGO1), and cell proliferation (CDK6), among others. Results showed that TNRC6B gene expression was up-regulated in PT tissue compared to N-PP (n = 52 paired samples) and could be useful for diagnostic purposes. Likewise, gene expression levels of CDK6, TNRC6B, and AGO1 were down-regulated in high-risk PT (n = 293) compared to low-risk PCa tissue counterparts (n = 172). When gene expression levels of CDK6, TNRC6B, and AGO1 were tested as a prognostic panel, the results showed that these improve the prognostic power of classical biomarkers. Conclusion ExomiRNAs-targets genes, TNRC6B, CDK6, and AGO1, showed a deregulated expression profile in PCa tissue and could be useful for PCa diagnosis and prognosis.

Abstract Background Cells have been increasingly known to release extracellular vesicles (EVs) to the extracellular environment under physiological and pathological conditions. A plethora of studies have revealed that EVs contain cell-derived biomolecules and are found in circulation, thereby implicating them in molecular trafficking between cells. Furthermore, EVs have an effect on physiological function and disease development and serve as disease biomarkers. Main body Given the close association between EV circulation and vascular disease, this review aims to provide a brief introduction to EVs, with a specific focus on the EV cargoes participating in pathological mechanisms, diagnosis, engineering, and clinical potential, to highlight the emerging evidence suggesting promising targets in vascular diseases. Despite the expansion of research in this field, some noticeable limitations remain for clinical translational research. Conclusion This review makes a novel contribution to a summary of recent advances and a perspective on the future of EVs in vascular diseases. Video Abstract

The realities of modern economic development require significant changes in the existing economic system and a transition to a fundamentally new model based on the basic approaches of sustainable development. According to the world’s scientists, one of the best options for ensuring this change is the concept of a “green” economy. The relevance of the topic of green economy development is based on its potential to solve urgent environmental problems and promote sustainable development that meets the needs of society and the international community. The purpose of the article is to assess the prospects of the agricultural sector of Ukraine’s economy within the framework of the transformation strategy based on the principles of the green economy. This takes into account a whole range of factors in which agricultural enterprises exist and develop, as well as the conditions that have developed in connection with military aggression in the country. To achieve this goal, the following methods were used: system-structural analysis, method of analysis, synthesis, method of generalization, methods of deduction and induction, and methodology of modified, improved SWOT analysis. A number of factors influencing the investment and innovation processes at agricultural enterprises are identified, including external threats and opportunities and internal strengths and weaknesses. The study also summarizes the aspects of the transition from the concepts of “sustainable” development to the concept of “greening” the economy, taking into account international experience, and the inclusion of Ukraine in the list of countries that ensure the fight against climate change and harmful emissions. The conclusions obtained about the prospects of investment projects in the agricultural sector, namely investment and innovation projects of agricultural enterprises characterized by a high level of attractiveness for investors in terms of the directional vector of development, confirm the relevance of implementing the concept of a green economy in the agricultural sector of Ukraine. The use of such an assessment methodology in practice will make it possible to select and analyse promising areas of project financing and investment, as well as to adjust the development strategies of Ukrainian agricultural enterprises

Abstract Background Andrographolide (Andro) is a diterpenoid derived from Andrographis paniculate, which has anti-inflammatory, antibacterial, antiviral and hepatoprotective activities. Gram-negative bacterial infections can cause varying degrees of liver injury in chickens, although Andro has been shown to have a protective effect on the liver, its underlying mechanism of action and effects on liver proteins are not known. Methods The toxicity of Andro on the viability of leghorn male hepatoma (LMH) cells at different concentrations and times was analyzed by CCK-8 assays. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in the culture supernatants were measured using an automatic biochemical analyzer to evaluate the protective effect of androscopolide on LPS-induced injury of LMH cells. Subsequently, TMT proteomics analysis were performed on the negative control group (NC group), LPS, and LPS-Andro groups, and bioinformatics analysis was performed on the differentially expressed proteins (DEPs). Results It was found that Andro reduced ALT and AST levels in the cell supernatant and alleviated LPS-induced injury in LMH cells. Proteomic analysis identified 50 and 166 differentially expressed proteins in the LPS vs. NC group and LPS-Andro vs. LPS group, respectively. Andro may be involved in steroid metabolic processes, negative regulation of MAPK cascade, oxidative stress, and other processes to protect against LPS-induced liver injury. Conclusions Andro protects against LPS-induced liver injury, HMGCS1, HMGCR, FDPS, PBK, CAV1, PRDX1, PRDX4, and PRDX6, which were identified by differential proteomics, may be the targets of Andro. Our study may provide new theoretical support for Andro protection against liver injury.

Abstract Background Afghanistan is suffering from 40‐year chronic conflicts, displacement, and demolition of its infrastructure. Afghanistan mortality survey 2010 shows nearly 46% of all deaths in the country were attributed to noncommunicable diseases (NCDs). In this study, we aimed to understand the differences in mortality and premature death due to NCDs by sex and the trend for the next 8 years. Methods We applied trend analysis using the secondary data from the Institute for Health Metrics and Evaluation, Global Burden of Diseases 2019. The information on NCD mortality, NCD deaths attributed to its risk factors, NCD percent of total years lived with disability (YLDs) attribution to each risk factor extracted from this database from 2008 to 2019. We investigated the trend from 2008 to 2019 for the mentioned factors and then forecast their trends until 2030. Results Our study shows that Afghanistan has had an increasing death number due to NCDs from 2008 to 2019 (50% for both sexes) and this will reach nearly 54% by 2030. Currently, half of NCDs deaths are premature in Afghanistan. The mortality rate and prevalence of risk factors are higher among women. More than 70% of YLDs will be due to NCDs in Afghanistan till 2030. Five risk factors including high systolic blood pressure (28.3%), high body mass index (23.4%), high blood glucose (20.6%), high low‐density lipoprotein cholesterol (16.3%), and smoking (12.3%) will have the highest contribution to NCDs death in 2030, respectively. Conclusions In general, our study indicates that without any specific intervention to address NCDs in Afghanistan, not only the Sustainable Development Goal target for NCDs will not be met, but an increase in almost all risk factors prevalence, as well as NCD mortality, will be seen in Afghanistan.

Yuqing Shen,1 Yuqi Zhu,1 Li Zhang,1 Jiayi Sun,1 Bo Xie,2 Hongyan Zhang,2 Xiuzu Song2 1Department of Dermatology, Hangzhou Third People’s Hospital, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Dermatology, Hangzhou Third People’s Hospital, Affiliated Hangzhou Dermatology Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Xiuzu Song, Hangzhou Third People’s Hospital, Hangzhou, People’s Republic of China, Email songxiuzu@sina.comObjective: To investigate the mechanism of minoxidil in treating androgenetic alopecia (AGA).Methods: The mechanism of action of minoxidil on AGA was first systematically investigated from the viewpoint of network pharmacology, including minoxidil-AGA target prediction, protein-protein interaction (PPI) network analysis, molecular docking and enrichment analysis of targets related to minoxidil and AGA, and dermal papilla cell assays to confirm the viability of prediction.Results: The combined analysis revealed that minoxidil treatment of AGA not only acts on androgenic receptors (AR) but also on 2 new targets, steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) and aromatase (CYP19A1). The biological processes linked to these targets were concentrated on several pathways, including enzymes and hormones. Further experiments have revealed that minoxidil suppresses the expression of AR and CYP17A1, boosts the activity of CYP19A1, decreases the formation and binding of dihydrotestosterone, and enhances the production of estradiol. Through these changes, minoxidil acts as a treatment for AGA.Conclusion: Minoxidil may act by altering hormonal and enzymatic pathways. Our study finds two new targets (CYP17A1, CYP19A1) of minoxidil and demonstrates that minoxidil inhibits AR. These targets may provide new ideas for drug research.Keywords: minoxidil, androgenetic alopecia, targets

To explore the function of licochalcone A as an anticancer phytochemical on HepG2 cells and investigate its potential mechanisms, we analyzed the microRNAs (miRNAs) expression profile of HepG2 cells in response to licochalcone A (70 μmol/L) in vitro. 102 dysregulated miRNAs were detected, and SP1 was expected as the transcription factor that regulates the functions of most screened miRNAs. A sum of 431 targets, the overlap of predicted mRNAs from TargetScan, miRDB, and miRtarbase were detected as the targets for these dysregulated miRNAs. FoxO signaling pathway was the hub pathway for the targets. A protein-protein interaction network was structured on the STRING platform to discover the hub genes. Among them, PIK3R1, CDC42, ESR1, SMAD4, SUMO1, KRAS, AGO1, etc. were screened out. Afterwards, the miRNA-target networks were established to screen key dysregulated miRNAs. Two key miRNAs (hsa-miR-133b and hsa-miR-145-5p) were filtered. Finally, the miRNA-target-transcription factor networks were constructed for these key miRNAs. The networks for these key miRNAs included three and two transcription factors, respectively. These identified miRNAs, transcription factors, targets, and regulatory networks may offer hints to understand the molecular mechanism of licochalcone A as a natural anticarcinogen.

In this paper, the robust !nite-time control for impact angle guidance of missile dynamic system with uncertainties is investigated by combining linear extended state observer (LESO) and adaptive non-singular fast terminal sliding mode method. Specially for dealing with existing uncertainties including time-varying parametric perturbation and nonparametric disturbances in high order line-of-sight rates and target acceleration, a robust LESO strategy is proposed for designing sliding mode-based impact angle guidance, which can guarantee that estimation error converges to the neighborhood of the origin in finite-time. Based on the proposed LESO framework, an adaptive non-singular fast terminal sliding mode guidance law is considered for realizing interception of maneuvering targets, which can guarantee asymptotically stability of the system. Simulation results are shown for confirming effectiveness of the proposed guidance strategy of this paper. Compared with former methods, accuracy of estimation is increased by nearly two times, and miss distance is reduced by nearly two times.

Abstract Obesity is a major risk factor for morbidity and mortality because it has a close relationship to metabolic illnesses, such as diabetes, cardiovascular diseases, and some types of cancer. With no drugs available, the mainstay of obesity management remains lifestyle changes with exercise and dietary modifications. In light of the tremendous disease burden and unmet therapeutics, fresh perspectives on pathophysiology and drug discovery are needed. The development of epigenetics provides a compelling justification for how environmental, lifestyle, and other risk factors contribute to the pathogenesis of obesity. Furthermore, epigenetic dysregulations can be restored, and it has been reported that certain natural products obtained from plants, such as tea polyphenols, ellagic acid, urolithins, curcumin, genistein, isothiocyanates, and citrus isoflavonoids, were shown to inhibit weight gain. These substances have great antioxidant potential and are of great interest because they can also modify epigenetic mechanisms. Therefore, understanding epigenetic modifications to target the primary cause of obesity and the epigenetic mechanisms of anti‐obesity effects with certain phytochemicals can prove rational strategies to prevent the disease and develop novel therapeutic interventions. Thus, the current review aimed to summarize the epigenetic mechanisms and advances in therapies for obesity based on natural products to provide evidence for the development of several potential anti‐obesity drug targets.